Clinical trials using single agent tumor necrosis factor have been ongoing for approximately the past 2 years. In vitro studies with TNF have demonstrated that the combination of interferon-gamma with tumor necrosis factor results in significant augmentation of antitumor effects. These results have been confirmed in vivo in animal models, however, it is not known if this enhancement is due to augmentation of the immune system. Substantial enhancement of TNF-related toxicity has also been observed using this drug in combination with interferon-gamma. In this study, we intend to investigate the immunomodulatory and toxic effects of the combination of TNF and interferon-gamma. Thirty-six patients have been treated on this study at nine different dose levels. Toxicities observed so far include fever, chills, headache, myalgia, fatigue, anorexia, nausea, vomiting, paresthesias, pain and erythema at the injection site of rTNF, moderate granulocytopenia and thrombocytopenia, moderate elevation in liver enzymes, and increases in fasting serum triglyceride levels. One patient experienced a mild cerebral infarct and was removed from the study. At dose level 9 (100 mcg/ml IFN-gamma/l00 mcg/ml rTNF), one patient had grade 4 fever, and another patient had grade 3 thrombocytopenia. The dose immediately below that, dose level 8, (100 mcg/ml rIFN-gamma/50 mcg/ml rTNF) was established as the maximum tolerated dose which should be investigated further in phase II trials. Minor antitumor activity was noted in two patients. An important finding of this study was the rTNF induced blunting of the expected monocyte activation by rIFN-gamma. No synergistic immunological effects were noted. Although enhanced immunomodulating effects were not observed, synergistic antitumor effects based on other mechanisms still may be observed in future phase II trials.